Defining Subcellular Specificity of Metabotropic Glutamate Receptor (mGluR5) Antagonists

Karen O'Malley

With $217,500 in grants from FRAXA Research Foundation, Dr. Karen O’Malley and team studied the function of mGluR5 when it is inside cells. Many of the symptoms of Fragile X Syndrome (FXS) are thought to arise due to overactive metabotropic glutamate receptor 5 (mGluR5) signaling, which is normally opposed by the protein missing in FXS, Fragile X Protein (FMRP).

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Fragile X Mutant Mouse Models

David Nelson, PhD, FRAXA Investigator

With $375,000 in grants from the FRAXA Research Foundation since 2009, Dr. David Nelson has developed an impressive array of advanced mouse models of Fragile X, at Baylor College of Medicine. These models are available to investigators worldwide on request. This resource has been essential for a broad, rapid distribution of Fragile X and related gene mouse models and has increased the pace of Fragile X research.

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Fruit Flies to Model and Test Fragile X Treatments

Dr. Tom Jongens and Dr. Sean McBride study Fragile X Fruit Flies

Dr. Jongens and his collaborators have found an insulin-like protein in the fly brain that is overexpressed in the Fragile X mutant fly, leading to increased activity of the insulin signaling pathway. Furthermore, they found that certain behavioral patterns in the Fragile X flies can be rescued by expressing the FX gene just in insulin producing neurons in the fly brain. In the mutant, there are other changes in the signaling pathways, including a decrease in cAMP and elevation in PI3K, mTOR, Akt and ERK activity. They now propose to study 2 medicines used for diabetes: pioglitazone (increases cAMP and decreases Akt and ERK) and metformin (inhibits mTOR), in flies and mice to validate the potential efficacy of these novel therapeutics for Fragile X.

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Treatment of Fragile X Syndrome via Dopamine Enhancers and Glutamate Inhibitors

Justin Cowan, PhD

FRAXA Awards $50,000 in 2011 and $50,000 in 2010 to Patricia Cogram, PhD for treatment of Fragile X syndrome via Dopamine Enhancers and Glutamate Inhibitors. This project aims to follow up our and others observations that the dopamine receptor is under expressed in the Fragile X syndrome and thus determine the effectiveness of targeted pharmacological treatments in Fragile X syndrome.

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A Developmental Switch Exists in the Effects of FMRP

Dr. Kimberly Huber

With a $90,00 grant from FRAXA Research Foundation for 2010-2011, Dr. Kimberly Huber and her team at the University of Texas at Southwestern found that there is a developmental switch of postsynaptic FMRP on synaptic function. This switch is controlled by MEF2 transcriptional activity. Proper synapse maturation and elimination is crucial for the establishment of appropriate neural circuits that underlie sensory processing and cognition. Neuron of Fragile X patients as well as in the mouse model of Fragile X, Fmr1 KO mice, display more dendritic spines, the point of contact for excitatory synapses, as well as long and thin filopodia resembling immature spines. This suggests Fragile X mental retardation protein (FMRP) has a role in promoting synapse maturation and elimination.

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Synaptic Actin Signaling Pathways in Fragile X

With a $163,356 grant from FRAXA Research Foundation in 2010-12, Dr. Scott Soderling and Dr. Hwan Kim at Duke University bred the standard mouse model of Fragile X syndrome to their lines of mice that express reduced levels of several key proteins that modulate synaptic actin. These compound mutant mice were compared to FXS mice to determine if genetically impairing pathways to the actin cytoskeleton can rescue deficits in the FXS mice.

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Inherited Channelopathies in Cortical Circuits of Fmr1 KO Mice

Andreas Frick, PhD

With this two year award of $90,000, Dr. Zhang and Principal Investigator Dr. Andreas Frick at Neurocentre Magendie in France investigated channelopathies using Fragile X mice. Many other proteins are misregulated as a result of the absence of FMRP. It is known that many ion channels, the pores in the cell membrane which allow neurons to conduct electrical impulses, have altered levels in Fragile X. This state is sometime called a “channelopathy” in the pharma world. This group is studying the effect of specific alterations in ion channels, and potential therapeutic effects of drugs which open and close these channels.

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Efficient Screening for Pharmaceutical Amelioration of FXS Behavioral Deficits in Drosophila

With a $112,250 grant from FRAXA Research Foundation over 3 years, Dr. Efthimios Skoulakis and his team from the Institute of Cellular and Developmental Biology conducted the first FRAXA project in Greece, where they developed a speedy new test for learning problems in fruit flies, which allowed them to test a number of drugs that are potential Fragile X treatments.

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Manipulating Basal and mGluR-Stimulated cAMP Level in FXS Model Mice

With a $90,000 grant from FRAXA Research Foundation, Dr. Hongbing Wang’s team from Michigan State University looked at a treatment target “downstream” of the mGluR5 called cyclic AMP (cAMP). Levels of cAMP are lower in FXS patients and animal models, suggesting that it plays a role in FXS. Drugs that raise levels of cAMP may effectively treat Fragile X. We are very pleased to report that, in 2012, Dr. Wang received a 5-year, $250,000 per year R01 grant from NIH to continue this promising research.

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